Basal Oral Insulin Analog I338 Enhances Meal-Related Hepatic Glucose Disposal

Oral insulin avoids the need for injections, and insulin enters via the hepatic portal vein (Po), the normal route of secretion. We examined the effect of I338, an acylated analog designed for oral use, dosed either Po to match the oral absorption profile or IV to match the steady state basal subcutaneous (SC) plasma profile, on a Po glucose challenge. To achieve steady-state concentrations in normal dogs, I338 was infused IV 45 min daily for 4 days. On day 5 a primed, continuous infusion of 3-3H glucose was given. After 90 min of equilibration and 30 min of basal sampling, a clamp was conducted (0-300 min), with somatostatin to inhibit pancreatic secretion and basal glucagon replacement. In the LOW dogs (n=5) I338 (pmol/kg/min) was infused either Po at 40 (0-45 min to mimic oral absorption) or IV at 1 (0-300 min to mimic subcutaneous [SC] delivery), approximately an equivalent daily dose (1800 vs. 1440 pmol/kg, Po vs. IV). High dose dogs (HI; n=4) received I338 at 50 (Po) or 5 (IV) pmol/kg/min. A Po glucose infusion mimicking meal absorption was given via computer algorithm from 30-252 min. All dogs were studied twice, 2 weeks apart in random order, receiving both Po and IV I338. Po vs. IV, respectively, resulted in: 1) lower glycemic levels (peak glucose LOW 6.2±0.3 and 10.3±0.6,* HI 4.5±0.3, and 7.8±0.8* mM); 2) increased net hepatic glucose uptake (AUC30-240 min Low 218.4±151.8 and -852.0±371.4,* HI 732.6±338.5 and -58.5±578.4* µmol/kg); 3) enhanced glucose clearance (AUC30-240 min LOW 481.9±29.7 and 359.4±33.7,* HI 874.3±99.8 and 495.3±25.9* mL/kg) and 4) greater peak hepatic fractional glucose extraction (LOW 0.05±0.02 and -0.01±0.01,* HI 0.10±0.and 0.04±0.02*)(*P